1. Field of the Invention
The present invention relates to a process for preparing distamycin derivatives and, more in particular, it relates to a process for preparing acryloyl-distamycin-guanidino derivatives, known to possess a remarkable antitumor activity.
2. Description of the Related Art
Distamycin A, whose formula is reported below belongs to the family of the pyrroleamidine antibiotics and it is reported to interact reversibly and selectively with DNA-AT sequences, thus interfering with both replication and transcription. See, for a reference, Nature, 203, 1064 (1964); FEBS Letters, 7 (1970) 90; Prog. Nucleic Acids Res. Mol. Biol., 15, 285 (1975).
Several analogues to distamycin are known in the art as antitumor agents.
As an example, the international patent application WO 98/04524 in the name of the Applicant itself, discloses distamycin derivatives, having valuable biological properties as antitumor agents, wherein the distamycin formyl group is replaced by an acryloyl moiety and the amidino group is replaced by several nitrogen-containing ending groups, among which is guanidino.
Specific examples of this class of acryloyl-distamycin-guanidino derivatives, optionally in the form of pharmaceutically acceptable salts, for instance as hydrochloride salts, are:
N-(5-{[(5-{[(5-{[(2-{[amino(imino)methyl]amino}ethyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrrole-2-carboxamide (internal code PNU 166196); and
N-(5-{[(5-{[(5-{[(2-{[amino(imino)methyl]amino}ethyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2-chloroacryloyl)amino]-1-methyl-1H-pyrrole-2-carboxamide.
These derivatives are prepared according to a chemical process comprising, essentially, the condensation reaction between a properly activated carboxylic acid derivative with a poly-pyrroleamido framework bearing the desired nitrogen-containing ending group, for instance the guanidino group.
This latter guanidino intermediate, in its turn, is prepared according to a rather troublesome step-by-step procedure which implies, substantially, several acylation reactions of 2-carboxy-4-amino-pyrroles which are obtained through reductions of the corresponding nitro derivatives, in a serial manner.
For a general reference to the above process for preparing acryloyl-distamycin derivatives, also including acryloyl-distamycin-guanidino derivatives see, for instance, the aforementioned WO 98/04524.